Anesthesia for Liver

Tra n s p l a n t a t i o n
a a b,
Dieter Adelmann, MD , Kate Kronish, MD , Michael A. Ramsay, MD, FRCA *

KEYWORDS

Liver transplantation
Anesthesia
Liver
Cirrhosis
End stage liver disease

Coagulopathy

KEY POINTS

Each program appoints a director of liver transplant anesthesia, who must meet the re-
quirements of the American Society of Anesthesiologists and the United Network for Or-
gan Sharing.

Liver cirrhosis may cause major dysfunction in all organ systems.

Cirrhotic cardiomyopathy may be masked by the typical high cardiac output and low pe-
ripheral vascular resistance often found in liver failure.

Portopulmonary hypertension and hepatopulmonary syndrome often found with liver
cirrhosis are at opposite ends of a vascular endothelial dysfunction pathway.

The proper management of the coagulopathy of a failing liver requires an understanding of
clot formation in “real time” and routine laboratory coagulation tests.

LIVER: BASIC ANATOMY AND PHYSIOLOGY

The liver is the largest internal organ in the body, receiving 25% to 30% of the cardiac
output. It has a dual blood supply. The hepatic artery provides 25% and the portal vein
provides 75% of the blood supply. Each vessel provides 50% of oxygen delivery. In
liver transplantation (LT), adequate flow through the hepatic artery is essential for
the viability of a new liver graft.1 Terminal branches of both the arterioles and venules
drain into sinusoids, where Kupffer cells filter and degrade particulate matter such as
endotoxins from the blood. Venous drainage is through hepatic veins into the inferior
vena cava. Bile canaliculi, between hepatocytes, form into bile ducts that drain into the
intestine.

D. Adelmann and K. Kronish have contributed equally to this article.

Disclosure Statement: None of the authors have financial disclosures related to this article.
a
Department of Anesthesiology and Perioperative Care, University of California San Francisco,
Box O648, 4th Floor MUE, 500 Parnassus Avenue, San Francisco, CA 94143, USA; b Department
of Anesthesiology, Baylor University Medical Center, 3500 Gaston Avenue, Dallas, TX
75246, USA
* Corresponding author.
E-mail address: docram@baylorhealth.edu

Anesthesiology Clin 35 (2017) 491–508

http://dx.doi.org/10.1016/j.anclin.2017.04.006 anesthesiology.theclinics.com
1932-2275/17/ª 2017 Elsevier Inc. All rights reserved.
492 Adelmann et al

The liver plays a major role in the metabolic pathway of carbohydrates, fats, and
proteins. Glucose is stored as glycogen and is converted by the liver to lactate, with
the generation of energy. Protein is metabolized to ammonia and urea, which is
then excreted in the urine. The liver also produces nearly all the plasma proteins,
except immunoglobulins. Notably, the liver produces albumin, which serves as the
most abundant plasma protein, the body’s primary transport protein and major deter-
minant of oncotic pressure. Another important liver function is drug metabolism, espe-
cially via the cytochrome p450 isoenzymes. The liver is also involved in hormone,
vitamin, and mineral metabolism.

LIVER DISEASE: PATHOPHYSIOLOGY

A thorough understanding of the pathophysiology of liver disease is required to care

for the liver transplant patient. The etiologies of the liver disease that most frequently
need transplantation are listed in Box 1.
In the United States, hepatitis C virus is currently the number one indication for LT,
with hepatic malignancy second. Given the new effective antiviral therapies for hepa-
titis C virus and the increasing obesity epidemic, nonalcoholic fatty liver disease is
likely to become the most common cause of liver disease in the United States in the
future.

Liver Cirrhosis
The term liver cirrhosis was coined by Rene Laennec in the 1840s. Hepatocellular
death can occur via necrosis or apoptosis, most often owing to ischemia, viruses,
and drug and alcohol toxicity. Cirrhosis refers to the damaging effects of inflammation,
hepatocellular injury, and the resulting fibrosis and regeneration of the liver, all of
which result in loss of normal liver function. Increased resistance to blood flow through
the liver leads to portal hypertension and the development of varices. The failing liver is
no longer able to clear the toxins that pass through it. Extensive endothelial dysfunc-
tion adversely affects all major organs.
Two commonly used scoring systems assess the severity of liver dysfunction. The
Child-Turcotte-Pugh (CTP) classification has been used to assess surgical risk in

Box 1
Common liver diseases that present at selection committee for possible transplantation

Viral Hepatitis
Alcoholic (Laennec’s) cirrhosis
Nonalcoholic steatohepatitis or nonalcoholic fatty liver disease
Hepatocellular cancer
Primary sclerosing cholangitis
Primary biliary cirrhosis
Autoimmune hepatitis
Cryptogenic cirrhosis
Drug induced (acetaminophen, amiodarone)
Acute liver failure
Genetic: amyloidosis, Wilson’s disease
 Anesthesia for Liver Transplantation 493

cirrhotic patients, and the Model for End-stage Liver Disease (MELD) score is vali-
dated to assess survival on the liver transplant waiting list.

The CTP score is calculated from:

Prothrombin time (seconds)
Encephalopathy
Ascites
Bilirubin (mg/dL)
Albumin (g/dL)
International Normalized Ratio (INR)

The MELD score calculation uses:

Serum creatinine (mg/dL)
Bilirubin (mg/dL)
INR

The sickest patients, who are most likely to die awaiting LT, receive highest waitlist
priority. The CTP severity score was initially used to allocate livers. In 2002, the MELD
score replaced the CTP score for liver allocation. It is a better predictor of 3-month
waitlist mortality and is less subjective. In 2016, serum sodium was added to the
MELD score for liver allocation, now called the MELD-Sodium. Higher waitlist priority
is also given to patients with certain disease processes, such as acute liver failure, pri-
mary nonfunction of a recently transplanted liver, and hepatocellular carcinoma.
These patients are given exception points because their increased waitlist mortality
is not reflected in the MELD score. Rules regarding scoring and exception points
are changing to attempt to address inequities in access.

TRANSPLANT SELECTION COMMITTEE

Before patients are accepted on the liver transplant waiting list, their suitability for
transplantation must be assessed by a selection committee. This committee includes
surgeons, hepatologists, anesthesiologists, and social workers. They focus on medi-
cal comorbidities, functional status, and a psychosocial evaluation. In the United
States alone, 40,000 patients die of liver disease each year, but only 6000 liver trans-
plants are performed annually. Thus, organ stewardship is extremely important. Selec-
tion committees are tasked with choosing patients with the greatest likelihood of
successful transplantation and posttransplant survival. The presence of anesthesiolo-
gists on selection committees is important to assess the perioperative risk. Contrain-
dications to transplantation include active alcohol and substance abuse, active
infection, malignancy outside of the liver, and the lack of social support and finances.
Advanced multiorgan system failure may be a contraindication to transplant, or may
require multiorgan transplantation. Given that deceased organ availability does not
meet waitlist demand, living donation of partial livers has emerged as alternative,
particularly for patients with low MELD scores.2
494 Adelmann et al

PREOPERATIVE ASSESSMENT

The patient admitted for possible LT has often spent many months on the waiting list.
At the time of transplantation, their MELD score might have increased significantly.
This patient may be significantly sicker than when they were discussed at the selection
committee. Therefore, all patients require careful reassessment by the anesthesiolo-
gist. If this patient is now too sick to be transplanted, the graft can be used to save
another life.
Some conditions that may critically affect the management of the liver recipient are
cirrhotic cardiomyopathy (CM), portopulmonary hypertension (POPH), hepatopulmo-
nary syndrome (HPS), acute tubular necrosis of the kidney, cerebral edema, and severe
electrolyte derangements. Competency with transesophageal echocardiography
(TEE), the availability for renal replacement therapy, and the ready access to consul-
tants are paramount.

CENTRAL NERVOUS SYSTEM: HEPATIC ENCEPHALOPATHY AND ACUTE LIVER FAILURE

Chronic liver dysfunction is associated with the accumulation of neurotoxins such as

ammonia, short chain fatty acids, and mercaptans. These toxins can bypass the liver
via portosystemic shunts. Their metabolism is impaired in liver dysfunction. In the cen-
tral nervous system, ammonia is metabolized to glutamine. Glutamine increases intra-
cellular osmolality and can lead to cerebral edema.3
Benzodiazepines should be used with care because they may potentiate this en-
cephalopathy and precipitate hepatic coma.
The nonabsorbable disaccharide lactulose and nonabsorbable antibiotics such as
rifaximin can reduce bacterial production of ammonia and treat hepatic encephalop-
athy in chronic liver disease.4 As liver failure progresses, encephalopathy may deteri-
orate to hepatic coma and cerebral edema develops (Box 2). Acute management of
hepatic encephalopathy consists of early intubation for airway protection to prevent

Box 2
Classification of hepatic encephalopathy

Unimpaired

No signs or symptoms

Normal psychometric or neuropsychological tests
Grades 0 to 1

Also known as minimal or convert hepatic encephalopathy

No overt clinical symptoms to mild decrease in attention span, awareness, altered sleep
rhythm

Abnormal psychometric or neuropsychological tests
Grade 2

Obvious personality change, inappropriate behavior, asterixia, dyspraxia, disorientation,
lethargy

Objectively disoriented to time
Grade 3

Somnolence, gross disorientation, bizarre behavior

Objectively disoriented to time and space
Grade 4

Coma

From Suraweera D, Sundaram V, Saab S. Evaluation and management of hepatic encephalop-

athy: current status and future directions. Gut Liver 2016;10(4):510; with permission.
 Anesthesia for Liver Transplantation 495

aspiration, maintain oxygenation, and prevent hypercarbia. Mild hypocapnia and mild
hypothermia may be helpful for neuroprotection.
In patients with cerebral edema, increased intracranial pressure can be managed by
the placement of an intracranial pressure monitoring system. The common indications
are papilledema, cerebral swelling, cardiovascular instability, and high ammonia
levels. Coagulopathy associated with acute liver failure puts patients at increased
risk for intracranial hemorrhage from the placement of invasive intracranial pressure
monitors. Administration of blood products, factor concentrates, or recombinant acti-
vated factor VII can mitigate this risk.5,6 Some centers use artificial liver support sys-
tems as a bridge to LT. Renal replacement therapy may be necessary to treat acidosis,
hyperkalemia, volume overload, and elevated ammonia and lactate levels.3,7

THE CARDIOVASCULAR SYSTEM

Cardiac dysfunction may be a consequence of liver disease, independent of liver dis-

ease or owing to a condition that affects both the heart and the liver. The typical he-
modynamic changes associated with cirrhosis are decreased systemic vascular
resistance and high cardiac output.8 Although the left ventricular ejection fraction
might be preserved, cardiac function in cirrhosis can be severely impaired. CM is diffi-
cult to identify, and clinicians not familiar with liver disease might mischaracterize the
heart function as that of a well-trained athlete when in fact it is severely weakened.
Therefore, cardiologists consulted should be very familiar with liver disease and its ef-
fects on the heart.

Cirrhotic Cardiomyopathy
Cardiomyopathy, characterized by systolic and diastolic dysfunction and electrophys-
iologic changes, may exist to some degree in all patients with liver cirrhosis.8–10 It
initially presents as a blunted response to b-adrenergic receptor agonists, so vaso-
pressor therapy may not be effective in traditional doses. CM is defined as an impaired
contractile responsiveness to physiologic or pharmacologic stress, impaired left ven-
tricular relaxation, and electrophysiologic abnormalities with prolonged QT inter-
val.8,11 Diagnostic criteria are presented in Table 1. Early onset of atrial fibrillation is
also common.12
Both systolic and diastolic dysfunction are best evaluated using echocardiography,
although a hyperdynamic circulation in the patient with liver cirrhosis can make the
echocardiographic examination more difficult. Previously undiagnosed CM can pre-
sent at the time of LT, with invasive monitoring showing low cardiac output in the pres-
ence of high filling pressures. TEE can help to assess for CM that may have developed
since the last evaluation.
Cardiac failure may be precipitated by the increased cardiac output that follows
transjugular intrahepatic portosystemic shunt placement or LT itself. The presence
of diastolic dysfunction has been associated with an increased risk of death in patients
with cirrhosis.13,14 Patients with CM are also at increased risk for graft failure or death
during LT.15,16 This cardiomyopathy is progressive without LT (Fig. 1). Successful
transplantation can reverse the effects of CM, although physiologic changes may
take up to 6 months to resolve.17

Primary Cardiac Disease

Coronary artery disease
All liver transplant waitlist patients should be screened for coronary artery disease (CAD).
Traditional risk factors include hypertension, smoking, diabetes, hypercholesterolemia,
496 Adelmann et al

Table 1
Diagnostic tests for cirrhotic cardiomyopathy

Methods Signs
Electrocardiogram
Prolonged QT interval
Exercise test
Reduced exercise tolerance
Cardiopulmonary exercise test
Alteration of aerobic capacity (peak VO2) or ventilatory
efficiency (VE/VCO2 or OUES)
Six-minute walk test
Reduced tolerance
Echocardiography
Systolic dysfunction (LVEF <55%)

Diastolic dysfunction

Left ventricular hypertrophy

Diastolic dysfunction (mean E/E0 index >10)
Exercise or dobutamine stress
Reduced contractile reserve
echocardiography
Magnetic resonance
Systolic dysfunction (LVEF <55%)

Diastolic dysfunction (peak filling rate)

Left ventricular hypertrophy
BNP/NT-proBNP
Elevated levels

Abbreviations: A wave, peak late atrial filling velocity (A, cm s1); BNP, brain natriuretic peptide;
EDT, E wave deceleration time (m/s); E wave, peak early filling velocity (E, cm s1); LVEF, left ventric-
ular ejection fraction; OUES, oxygen uptake efficiency slope; proBNP, prohormone brain natriuretic
peptide; VE, ventilator efficiency; VE/VCO2, minute ventilation/carbon dioxide production; VO2,
oxygen volume (oxygen consumption); VCO2, carbon dioxide production.
From Zardi EM, Zardi DM, Chin D et al. Cirrhotic cardiomyopathy in the pre- and post-liver trans-
plantation phase. J Cardiol 2016;67(2):128; with permission.

Fig. 1. The progression of cirrhotic cardiomyopathy. GI, gastrointestinal; LV, left ventricular;
SVR, systemic vascular resistance; TIPS, transjugular intrahepatic portosystemic shunt. (From
Zardi EM, Zardi DM, Chin D et al. Cirrhotic cardiomyopathy in the pre- and post-liver trans-
plantation phase. J Cardiol 2016;67(2):127; with permission.)
 Anesthesia for Liver Transplantation 497

obesity, and genetic history. These comorbidities are especially likely in patients with
nonalcoholic fatty liver disease. The prevalence of CAD in transplant candidates with
2 or more traditional risk factors is 50%.18–20 In patients who receive adequate treatment
for CAD before transplantation, postoperative outcomes are comparable to patients
without CAD.21
Hypertrophic cardiomyopathy can increase perioperative cardiovascular complica-
tions in patients presenting for LT. Strategies for successful management include pre-
operative alcohol septal ablation, and careful intraoperative management using TEE to
optimize contractility and heart rate.22,23
Diseases affecting both the liver and the heart include alcoholic disease, amyloid
disease, obesity, and hemosiderosis. Combined heart transplantation and LT can
be considered if the risk of single organ transplant is high, such as in patients with fa-
milial amyloid disease.24

Preoperative Cardiac Assessment

Cardiac testing for all patients evaluated for LT should include an electrocardiogram
and transthoracic echocardiography.25 A prolonged QT interval and atrial fibrillation
can be detected using an electrocardiogram. Impaired diastolic function can be
detected using left ventricular inflow velocities (E:A ratio) and tissue Doppler (E:E0 ratio,
velocity of myocardial displacement).11 Dobutamine stress echocardiography and
myocardial perfusion scintigraphy are widely used to assess left ventricular function
and screen for ischemic heart disease. In patients with multiple risk factors or when
noninvasive testing is suggestive of ischemia, coronary angiography is indicated for
diagnosis and possible treatment.25

PULMONARY SYSTEM

Pulmonary dysfunction affects up to 50% of patients with liver disease. The major pul-
monary concerns are: refractory hepatic hydrothorax, HPS, POPH, hemorrhagic he-
reditary telangiectasia, interstitial lung disease, and alpha-1-antitrypsin deficiency-
related emphysema.

Hepatic Hydrothorax
Cirrhosis can cause a restrictive ventilation defect. Ascites passes into the pleural
space through defects in the diaphragm and leads to pleural effusions. Conservative
management includes diuretic therapy and salt restriction. Thoracentesis and pleural
catheters may be indicated in refractory patients.26 Hepatic hydrothorax is reversible
after LT.
The pulmonary vascular endothelium is a vital organ that impacts vasoregulation,
the fluidity, antithrombosis, laminar blood flow, permeability, and growth of the sur-
rounding smooth muscle. Portal hypertension exposes the pulmonary vascular endo-
thelium to inflammatory cytokines and stress forces owing to high laminar flow. This
leads to endothelial dysfunction with either a predominantly vasodilatory pulmonary
circulation (HPS) or a restrictive, vasoconstrictive circulation resulting in POPH (Fig. 2).
HPS is characterized by a triad of a decreased oxygen saturation in the presence of
advanced liver disease and intrapulmonary vascular dilatation. It is present in 5% to
30% of patients evaluated for LT. Pulmonary arteriovenous shunts and capillary vaso-
dilation caused by portal hypertension lead to a reduced capillary transit time and
diminished oxygen diffusion.27–29 The end result is that many of the red cells are not
fully saturated with oxygen.
498 Adelmann et al

Fig. 2. Pathophysiology of the hepatopulmonary syndrome and portopulmonary hyperten-

sion. a Worsening cirrhosis or sepsis lead to a further reduction in Systemic Vascual Resistance
(SVR), whereas a rapid increase in SVR is seen after liver transplant. CO, carbon monoxide;
eNOS, endothelial nitric oxide synthase; ETB, endothelin type B; HO-1, heme oxygenase 1;
iNOS, inducible nitric oxide synthase; NO, nitric oxide; TNF-a, tumor necrosis factor alpha;
VEGF, vascular endothelial growth factor. (Adapted from Surani SR, Mendez Y, Anjum H,
et al. Pulmonary complications of hepatic diseases. World J Gastroenterol 2016;22(26):6010;
with permission.)

Pulse oximetry can be used to screen for HPS. Oxygen saturations (SpO2) of less
than 96% require further evaluation. Diagnosis is confirmed by transthoracic echocar-
diography showing a delayed right-to-left shunt using agitated saline. After adminis-
tration of agitated saline into the venous system, contrast microbubbles appear in
the left heart after a delay of 3 to 6 heart beats; with intracardiac shunts, contrast
microbubbles are seen moving from the right to left heart immediately. The decrease
in oxygen content is defined by an increased alveolar–arterial oxygen gradient of equal
to or greater than 15 mm Hg while breathing room air in the sitting position.29
Clinical signs in patients with HPS are digital clubbing, cyanosis, and platypnea
(dyspnea that is worse upon moving from supine to upright position). This form of dys-
pnea is unique to HPS. Patients diagnosed with HPS have a 2-fold increased risk of
mortality compared with cirrhotic patients without HPS. They are granted MELD
exception points for higher waitlist priority. There is currently no medical treatment
for HPS.
In severely hypoxic patients, extracorporeal membrane oxygenation can facilitate
successful LT.30 After transplantation, resolution of HPS can be expected within 1
to 2 years.31
POPH results when the pulmonary vascular endothelium is exposed to inflammatory
cytokines, including endothelin-1. This leads to vasoconstriction, proliferation of
 Anesthesia for Liver Transplantation 499

endothelium and smooth muscle, and platelet aggregation. Eventually fibrosis results.
This obstruction to flow leads to pulmonary hypertension and right heart failure. The
severity of POPH is graded based on right heart catheterization data (Table 2).
Adequate right ventricular (RV) function is essential for survival during LT. Even mild
RV dysfunction can cause the new liver graft to become congested and fail. Severe RV
dysfunction can lead to intraoperative death.32 The use of venous–arterial extracorpo-
real membrane oxygenation improves survival in this patient group. Both POPH and
HPS may exist together; however, POPH may not reverse after LT.33
All LT candidates must be screened for POPH. The prevalence is about 5%.34 An RV
systolic pressure of greater than 50 mm Hg and/or significant RV hypertrophy or
dysfunction is an indication for right heart catheterization to characterize the pulmo-
nary hemodynamics. True POPH must be differentiated from pulmonary hypertension
generated from high cardiac output, volume overload, or venous hypertension (Fig. 3).
Without treatment, POPH is associated with a 1-year survival of 35% to 46%.35,36
The medical treatment for POPH is improving. There are 3 therapeutic classes avail-
able: prostacyclin analogues, phosphodiesterase inhibitors, and endothelin receptor
antagonists. Mild POPH presents with normal perioperative risk for LT. Moderate
POPH is associated with increased perioperative mortality, and severe POPH is
considered a contraindication to LT. Patients with severe POPH can undergo LT
only if their pulmonary arterial pressures can be lowered using medical therapy and
if RV function is adequate.
Patients diagnosed with POPH in the operating room immediately before LT should
have an assessment of RV function by TEE. If there is evidence of RV dysfunction, LT
must be deferred. Patients with a mean pulmonary artery pressure of less than 35 mm
Hg and a PVR of less than 240 dyn.sec.cm5 can safely undergo LT. Reperfusion is the
most critical period during LT. Cardiac output can significantly increase with reperfu-
sion, causing an acute increase in the mean pulmonary artery pressure, which can
lead to RV failure. The following interventions have salvaged some transplants: inhaled
nitric oxide, intravenous or inhaled prostacyclins, milrinone, and extracorporeal mem-
brane oxygenation.37

THE RENAL SYSTEM

Hepatorenal syndrome (HRS) is a functional renal impairment in patients with

advanced liver disease or severe fulminant liver injury. It is characterized by increased
renal vasoconstriction, a reduced glomerular filtration rate, subsequent increase in
creatinine, and impaired sodium and water excretion.
Portal hypertension leads to profound systemic and splanchnic vasodilatation and
intravascular volume depletion. This increases renal vasoconstriction via both the
renin–angiotensin–aldosterone pathway and sympathetic nervous system activation.
Renal vasoconstriction leads to significant hypoperfusion of the kidney.38 HRS is

Table 2
Classification of portopulmonary hypertension

Mean Pulmonary Pulmonary Vascular Pulmonary Capillary

Artery Pressure (mm Hg) Resistance (dyn.sec.cmL5) Wedge Pressure (mm Hg)
Normal <25 — —
Mild 25–35 >240 <15
Moderate 35–45
Severe >45
500 Adelmann et al

Fig. 3. (A–D) Etiologies of pulmonary hypertension in the liver transplant candidate. Only (B)
is true portopulmonary hypertension. PAH, pulmonary arterial hypertension; PCWP, pulmo-
nary capillary wedge pressure; PVR, pulmonary vascular resistance. (From Safdar Z, Bartolome
S, Sussman N. Portopulmonary hypertension: an update. Liver Transpl 2012;18(8):883; with
permission.)

classified as type 1, with rapid deterioration in renal function, and type 2 with a more
gradual deterioration in renal function. Type 1 HRS has a 2-week mortality of about
80% whereas in type 2 HRS, kidney function declines more slowly and survival rates
without LT are around 6 months. The diagnosis is based on the absence of primary
kidney disease, proteinuria, or systemic hypovolemia causing renal hypoperfusion.
There is normal urinary sediment, low urinary sodium (<10 mEq/L), uremia, and oligu-
ria. Unfortunately, serum creatinine is a poor marker for renal dysfunction in HRS
because these patients are usually cachectic with poor muscle mass. HRS type 1
can be treated with albumin in combination with the vasoconstrictor terlipressin.38
Other vasoconstrictors used are vasopressin, the alpha-adrenergic receptor agonist
midodrine, and norepinephrine. Renal replacement therapy may be used to stabilize
the HRS patients before LT. HRS is reversible with LT. Prolonged endothelial damage
can lead to irreversible tubular necrosis. A combined liver–kidney transplant should
then be considered (Fig. 4).

THE COAGULATION SYSTEM

Liver disease has a complex effect on coagulation. It is widely understood to increase

risk of bleeding: hepatic synthesis of procoagulant factors such as the vitamin K–de-
pendent coagulation factors II, VII, IX, and X are reduced, and thrombocytopenia is
common. However, the liver also produces the anticoagulant factors protein C, protein
S, and antithrombin III, which are reduced in liver disease. Coagulation factor VIII,
which is synthesized in the endothelium, is increased in patients with liver disease.
Despite low platelet counts, platelet adhesion and aggregation might be normal,
because of increased endothelial production of von Willebrand factor.39–41 Thus,
 Anesthesia for Liver Transplantation 501

Fig. 4. The basic mechanism of the hepatorenal syndrome. GFR, glomerular filtration rate;
NASH, nonalcoholic steatohepatitis; SNS, sympathetic nervous system; TIPS, transjugular in-
trahepatic portosystemic shunt. (From Shah N, Silva RG, Kowalski A, et al. Hepatorenal syn-
drome. Dis Mon 2016;62(10):367; with permission.)
502 Adelmann et al

coagulation dysfunction in liver disease can better be described as a fragile balance

between low levels of both procoagulation and anticoagulation factors.40 During LT,
both bleeding as well as thromboembolic complications may occur (Table 3).
Adequate coagulation requires sufficient amounts of thrombin. Thrombin then triggers
the formation of a strong clot made of fibrinogen and platelets that can withstand fibri-
nolysis. The INR, although often used to assess the risk of bleeding in patients with
liver disease, provides only a partial picture of the state of coagulation.2
Point-of-care global viscoelastic coagulation tests such as thromboelastography
(Haemonetics Corporation, Braintree, MA) and thromboelastometry (TEM Interna-
tional GmbH, Munich, Germany) can help to evaluate clot formation in whole blood.
Thromboelastography/thromboelastometry can determine the quality of clot forma-
tion (generation of thrombin), clot strength (the effect of fibrinogen and platelets),
and fibrinolysis.42–44 The degree of coagulopathy varies widely with the underlying
liver disease. Patients with hepatocellular carcinoma often have normal coagulation
profiles. Despite a prolonged INR, some patients show a hypercoagulable profile in
thromboelastography. This could likely indicate an increased risk for thromboembolic
complications.45
In addition, bleeding in patients with liver disease is not always owing to coagulop-
athy. Other common causes include portal hypertension and varices, endothelial
dysfunction, renal failure, and disseminated intravascular coagulation.46

ANESTHESIA MANAGEMENT

Except for elective living donor liver transplants, the majority of liver transplants are
performed as emergency cases. Many recipients have multiorgan dysfunction at the
time of transplantation.
Basic intraoperative monitoring includes central venous and intraarterial pressure
monitoring. In patients with suspected cardiac dysfunction or POPH, pulmonary artery
catheter placement and/or TEE may be indicated. Echocardiography is a powerful tool
to assess major hemodynamic changes and guide inotropic therapy. It also can detect
major complications early such as intracardiac thromboembolism or air embolism.47
The use of thromboelastography for coagulation monitoring and ultrasound guid-
ance for vascular catheter placement are center specific. Rapid infusion devices
and red cell salvage systems are used in some centers. The availability of a rapid

Table 3
Hemostatic system alterations that contribute to bleeding or hemostasis

Changes That Impair Hemostasis Changes That Promote Hemostasis

Thrombocytopenia
Platelet function defects
Enhanced production of nitric oxide and
prostacyclin
Low levels of factors II, V, VII, IX, X, and XI
Vitamin K deficiency
Dysfibrinogenemia
Low levels of a2-antiplasmin, factor XIII, and
thrombin-activatable fibrinolysis inhibitor
Elevated tissue plasminogen activator levels
Elevated levels of von Willebrand factor
Decreased levels of ADAMTS-13
Elevated levels of factor VIII
Decreased levels of protein C, protein S,
antithrombin, a2-macroglobulin, and
heparin cofactor II
Low levels of plasminogen

From Lisman T, Caldwell SH, Burroughs AK, et al. Hemostasis and thrombosis in patients with liver
disease: the ups and downs. J Hepatol 2010;53(2):363; with permission.
 Anesthesia for Liver Transplantation 503

response laboratory service with rapid turnaround times and blood bank services are
essential.48
Electrolyte derangements should be monitored closely. With the new MELD-
Sodium scoring system, more patients with hyponatramia are likely to be transplanted.
If serum sodium is increased too rapidly, central pontine myelinolysis can occur.
The operation is divided into 3 phases: preanhepatic, anhepatic, and the neohepatic
phases. During the preanhepatic phase, the native liver is dissected and then
removed. Blood loss during this phase can be considerable. Compression or occlu-
sion of major blood vessels can cause further hemodynamic compromise. This phase
ends in the clamping of the inferior vena cava, portal vein and hepatic artery, and
removal of the liver.
There are 3 basic surgical techniques for liver transplant:
A. Total occlusion of the vena cava and the portal vein (“full clamp,” Fig. 5): This re-
sults in a severe reduction in venous return to the heart during the anhepatic phase.
The presence of portal varices and other new vessels in patients with longstanding
cirrhosis can ameliorate this effect. Care must be taken not to overcompensate
with significant volume expansion, because this volume will return to the circulation
upon unclamping. The resulting hypervolemia can lead to venous congestion and
poor function of the new liver.

Fig. 5. Liver transplant with replacement of the vena cava (“full clamp”). (From Dienstag JL,
Cosimi AB. Liver transplantation — a vision realized. N Engl J Med 2012;367(16):1484; with
permission.)
504 Adelmann et al

B. “Piggy-back” technique: The inferior vena cava is only partially occluded with a
side-biting clamp. The portal vein is still fully clamped throughout the anhepatic
phase. With partial return of blood from the inferior vena cava to the heart, hemo-
dynamics are usually more stable than with a full clamp.
C. Venovenous bypass: Venous blood from the inferior vena cava and femoral vein is
returned into the internal jugular vein using extracorporeal venovenous cannulas
and a centrifugal pump. Care must be taken to avoid air emboli, thromboembolism
and hypothermia. In theory, this approach might be renoprotective and cause less
cardiac strain. But clinical trials proving this advantage are currently lacking. The
use of this practice seems to be decreasing.49
During the anhepatic phase, the new liver is anastomosed into place and reper-
fused. As the vena cava is unclamped, adequate return of venous blood volume to
the heart is restored. Blood pressure and cardiac output improve. The portal vein is
then opened, causing the cold, acidotic, hyperkalemic blood from below the clamp
and from the liver graft itself to circulate directly into the right heart. This can cause
a significant decrease in blood pressure, bradycardia, other arrhythmias, and occa-
sionally cardiac arrest. Severe hypotension upon unclamping is called reperfusion
syndrome and can be ameliorated by administration of calcium chloride, bicarbonate,
epinephrine, and vasopressin.50 The time taken to sew the new graft in place is the
warm ischemia time. Warm ischemia is very damaging to the graft, and thus limiting
warm ischemia time is critical to graft function.
The neohepatic phase consists of the hepatic artery and bile duct anastomoses,
often with a concomitant cholecystectomy. During this time, the anesthesiologist is
looking for signs that the new liver is beginning to function—improvement in acidosis
and clearing of lactic acid, and improved hemostasis and production of bile. Hemosta-
sis requires excellent surgical skills, temperature control and the early diagnosis and
treatment of fibrinolysis. Failure to do so leads to breakdown of existing clots and the
development of diffuse bleeding.
Maintenance of a low central venous pressure may reduce venous bleeding during
hepatectomy.51,52 For patients with severe portal hypertension, octreotide infusion
may be indicated to reduce the portal venous pressure.53 Vasopressors commonly
used during LT are norepinephrine, vasopressin, and epinephrine.54 Ionized calcium
frequently decreases and needs to be replaced.
Treatment of abnormal laboratory values such as low platelet counts, low fibrin-
ogen, and high prothrombin times is only required if there is clinical bleeding. These
laboratory values frequently normalize as the new graft functions and platelets return
to the circulation from the spleen. In case of bleeding, patients are treated with factor
replacement, blood, and platelets. Approaches to resuscitation and treatment of high
blood loss differ by institution.
Renal dysfunction, with poor urine output and rising creatinine, may occur during
transplantation, especially after a full caval clamp, long anhepatic time, or prolonged
hypotension. Patients with volume overload, hyperkalemia, or hyponatremia may
benefit from continuous venovenous hemodialysis that can be instituted in the oper-
ating room or upon arrival to the intensive care unit.

POSTOPERATIVE COURSE

Early extubation is feasible in select patients after LT.55 The new graft must show good
function by beginning clearance of acidosis and falling lactate levels. Monitoring of
neuromuscular blockade is essential before extubation. Patients must also be coop-
erative, and pain must be controlled adequately. They must meet usual standard
 Anesthesia for Liver Transplantation 505

extubation criteria. In some institutions, extubated patients with good liver function
can bypass the intensive care unit and are sent to the postoperative recovery unit
and then to a regular surgical floor or step-down unit.
Occasionally, the abdominal distension owing to an especially large organ or tissue
swelling might prevent primary closure of the surgical wound. These patients are at
risk for abdominal tamponade. Abdominal closure can be delayed for several days af-
ter transplantation to prevent abdominal compartment syndrome.
Measures must be taken to avoid central line-associated infections. Invasive lines
should be removed as soon as appropriate. Function of the new graft must be moni-
tored closely, looking especially for signs of infection, bleeding, and acute rejection.
Some patients with bleeding or graft dysfunction may require emergent return to
the operating room. Patients may have a difficult postoperative course with significant
multiorgan dysfunction, and these patients require expert intensive care.

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